This invention relates to a tetrahydrobenzindole compound. Since this tetrahydrobenzindole compound binds to serotonin receptors in the living body, it also relates to the treatment and prevention of diseases which are induced by the abnormality of serotonin controlling functions, such as manic-depressive psychosis, anxiety, schizophrenia, sleep disorders, jet lag, gastrointestinal disease, cardiovascular disease and the like.
In the present society, the environment which surrounds us is sharply changing, and adaptation for it is becoming more and more difficult. Thus, a part which is too much for adaptation for the social environment is accumulated in our bodies as stress and sometimes causes abnormality of not only physical functions but also mental functions. In the treatment of abnormal mental functions, importance of drug therapy has been increasing more and more in addition to psychological therapy, so that development of effective drugs has been put forward.
Since the indication about the action of serotonin (5-HT) in the central nervous system, classification and distribution of serotonin receptors have been revealed gradually. By the detailed analysis of serotonin receptors using molecular biological technique in recent years, 5-HT1 and its subtypes, 5-HT2 and its subtypes, 5-HT3, 5-HT4, 5-HT6, 5-HT7 and the like have been specified and a total of 14 different serotonin receptors have been proposed [R. D. Ward et al., Neuroscience, Vol. 64, pp. 1105-1111 (1995)]. Studies on the physiological functions of serotonin receptors have also been making progress, and not only their relation to appetite, body temperature regulation, blood pressure regulation and the like body functions but also their relation to depression, anxiety, schizophrenia, sleep disorders and the like mental functions have been revealed [P. L. Bonate et al., Clinical Neuropharmacology, 14, pp. 1-16 (1991)]. Actually, 5-HT1A receptor agonists, 5-HT2 receptor inhibitors and 5-HT re-uptake inhibitors are now used in the clinical field.
It has been reported also that, since serotonin receptor 5-HT6 has the affinity particularly for a drug group classified as atypical among already known schizophrenia treating drugs, the serotonin receptor 5-HT6 is closely related to the efficacy of these drugs [R. D. Ward et al., Neuroscience, Vol. 64, pp. 1105-1111 (1995)].
Roth B. L. et al. [J. Pharmacol. Exp. Ther., 1994, 268 (3), 163-170] have reported that several atypical schizophrenia treating drugs including clozapine have strong affinity for the 5HT6 receptor, and several typical schizophrenia treating drugs show high affinity for both of the 5HT6 and 5HT7 receptors.
Also, Tollefson G. D. et al [Psychopharmacol. Bull., 1991, 27, 163-170] have reported that a 5HT1A partial agonist, buspirone, has high therapeutic effect for patients having both symptoms of depression and anxiety.
In addition, L. M. Caster et al. [J. Med. Chem., Vol. 38, 4760-4763 (1994)] have reported that certain N-butylpiperidines inhibit serotonin receptor 5-HT4 selectively and are useful for the treatment of irritable digestive organ syndrome, and T. W. Lovenberg et al. [Neuron, Vol. 11, 449-458 (1993)] have assumed that serotonin receptor 5-HT7 exerts an important function in the human circadian rhythm regulation.
As has been described in the above, functions of serotonin receptors are being revealed, so that great concern is directed toward the creation of a chemical substance which exerts its function upon one of these serotonin receptors or simultaneously upon a plurality of these serotonin receptors, because it will provide pharmaceutical preparations which are useful not only for the physiological studies on the function of central and peripheral nervous systems but also for the treatment and prevention of various diseases which are considered to be induced by the abnormality of intracerebral and peripheral serotonin controlling functions, such as schizophrenia, manic-depressive psychosis, anxiety, sleep disorders, jet lag, gastrointestinal disease, migraine and abnormal blood pressure and the like cardiovascular disease.
The present invention comprises the following constructions.
1. A compound represented by formula (I): 
[wherein A represents N, CH, C having a double bond or CR5; each of B and Z independently represents N or CR1, with the proviso that A is N when B and/or Z is N; R1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a trihalomethyl group, a hydroxy group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group, an acyl group or a carboxy group; R2 represents a hydrogen atom or a lower alkyl group; R3 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R4 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, a nitro group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group or an acyloxy group; R5 represents a lower alkyl group, a cyano group, a carbamoyl group, a carboxy group, an acyl group, an acyloxy group, an alkoxy group, an alkoxycarbonyl group, a trihalomethyl group or a hydroxy group; and n is an integer of 2 to 6] or a pharmaceutically acceptable salt thereof.
2. A compound according to the aforementioned item 1, which is represented by formula (II): 
[wherein Y represents N or CH; and R1, R2, R3, R4 and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
3. A compound according to the aforementioned item 1, which is represented by formula (III): 
[wherein R1, R3, R4 and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
4. A compound according to the aforementioned item 1, which is represented by formula (IV): 
[wherein R1, R2, R3, R4, R5 and n are as defined in the foregoing] or a pharmaceutically acceptable salt thereof.
5. A compound according to the aforementioned item 1, which is represented by formula (V): 
[wherein R1, R3, R4, Z and n are as defined in the foregoing; and R1 is preferably a hydrogen atom, a lower alkyl group, a trihalomethyl group or an alkoxy group] or a pharmaceutically acceptable salt thereof.
6. A compound represented by formula (a-1): 
[wherein X represents a halogen atom, a methanesulfonyloxy, ethanesulfonyloxy or the like alkylsulfonic acid ester residue or a benzenesulfonyloxy group, p-toluenesulfonyloxy or the like arylsulfonic acid ester residue; and R3, R4 and n are as defined in the foregoing].
7. A pharmaceutical composition for use in the treatment or prevention of mental diseases, which contains any one of the compounds of the aforementioned items 1 to 5 or a pharmaceutically acceptable salt thereof.
The compounds which are provided by the present invention can be produced by the chemical synthesis methods described below. In the following descriptions concerning the chemical substances of the present invention and production methods thereof, the term xe2x80x9chalogen atomxe2x80x9d means fluorine, chlorine, bromine or iodine atom, the term xe2x80x9clower alkylxe2x80x9d means a methyl, ethyl or the like straight chain alkyl group having 1 to 4 carbon atoms, an isopropyl, isobutyl, t-butyl or the like branched-chain alkyl group or their halogen-substituted alkyl group, and the term xe2x80x9cbase to be used as a catalystxe2x80x9d means sodium hydroxide, potassium carbonate, triethylamine or the like.
In the formula (I), R1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a cyano group, a trihalomethyl group (wherein the three halogen atoms are as defined in the foregoing and may be the same or different from one another, and a trifluoromethyl group is preferred), a hydroxy group, an alkoxy (preferably having 1 to 4 carbon atoms, such as methoxy and ethoxy), an alkylthio group (preferably having 1 to 4 carbon atoms, such as methylthio and ethylthio), a alkylsulfinyl group (preferably having 1 to 4 carbon atoms), an alkylsulfonyl group (preferably having 1 to 4 carbon atoms), an alkoxycarbonyl group (preferably having 1 to 4 carbon atoms), a sulfamoyl group, an amino group, a substituted amino group (preferably an amino substituted with a lower alkyl, such as dimethylamino and diethylamino), a carbamoyl group, an alkylcarbamoyl group (preferably the alkyl moiety is a lower alkyl, such as dimethylcarbamoyl), an acyl group (preferably having 1 to 4 carbon atoms, such as acetyl) or a carboxy group; R2 represents a hydrogen atom or a lower alkyl group; R3 represents a hydrogen atom, a lower alkyl group or an aralkyl group (such as benzyl); R4 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group (preferably having 1 to 4 carbon atoms, such as methoxy and ethoxy), an acyl group (preferably having 1 to 4 carbon atoms, such as acetyl), an alkoxycarbonyl group (preferably having 1 to 4 carbon atoms, such as methoxycarbonyl and ethoxycarbonyl), a nitro group, an amino group, a substituted amino group (preferably an amino substituted with a lower alkyl, such as dimethylamino and diethylamino), a carbamoyl group, an alkylcarbamoyl group (preferably the alkyl moiety is a lower alkyl, such as dimethylcarbamoyl) or an acyloxy group (preferably having 1 to 4 carbon atoms, such as acetoxy); and R5 represents a lower alkyl group, a cyano group, a carbamoyl group, a carboxy group, an acyl group (preferably having 1 to 4 carbon atoms, such as acetyl), an acyloxy group (preferably having 1 to 4 carbon atoms), an alkoxy group (preferably having 1 to 4 carbon atoms, such as methoxy and ethoxy), an alkoxycarbonyl group (preferably having 1 to 4 carbon atoms), a trihalomethyl group (wherein the three halogen atoms are as defined in the foregoing and may be the same or different from one another, trifluoromethyl is preferred) or a hydroxy group.
These substituent groups in the aforementioned formula (I) can be applied to the substituent groups to be used in the other formulae (II) to (V)
In addition, in the general formula (I), R1 can be substituted independently for all hydrogen atoms on the ring (including a case in which B and Z are CR1) so that even if it is entirely unsubstituted with substituent groups other than a hydrogen atom, it can be substituted with the same or different substituent groups other than a hydrogen atom at one position or a plurality of positions. Such a general idea of substituent groups can be applied to R4 and also to the substituent groups to be used in the other formulae (II) to (V).
The compound of the present invention represented by the formula (I) (hereinafter, referred to as compound (I), the compounds represented by other formulae are also expressed in the same manner) can be obtained by reacting a compound (a-1) with a compound (b). 
(In the above reaction formula, A, B, Z, R1, R2, R3, R4, X and n are as defined in the foregoing.)
The reaction for obtaining the compound (I) is carried out in the presence or absence of a base (however, a material substance is excluded as will be described later) without solvent or after dilution with an inert solvent and progresses at a temperature within the range of from ordinary temperature to heating temperature.
Examples of the inert solvent to be used include alcohols such as ethanol, ketones such as acetone or methyl ethyl ketone, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide and the like, and examples of the base include salts of alkali metals such as sodium carbonate, potassium carbonate and the like carbonates and sodium bicarbonate, potassium bicarbonate and the like bicarbonates, trialkylamines, pyridine bases, and the like, as well as the compound (b) itself which is a secondary amine to be used as a material substance but can also be used as a base when used in an excess amount. In this connection, the base also exerts its functions as a reaction catalyst and an acid absorbent which neutralizes an acid formed as a result of the reaction.
The compound (II) can be obtained by allowing the compound (a-1) and a compound (b-1) to react with each other in accordance with the reaction conditions for the formation of compound (I). 
(In the above reaction formula, Y, R1 and R2 are as defined in the foregoing.)
The compound (III) can be obtained by allowing the compound (a-1) and a compound (b-2) to react with each other in accordance with the reaction conditions for the formation of compound (I). 
(In the above reaction formula, R1 is as defined in the foregoing.)
The compound (IV) can be obtained by allowing the compound (a-1) and a compound (b-3) to react with each other in accordance with the reaction conditions for the formation of compound (I). 
(In the above reaction formula, R1 and R5 are as defined in the foregoing.)
The compound (V) can be obtained by allowing the compound (a-1) and a compound (b-4) to react with each other in accordance with the reaction conditions for the formation of compound (I). 
(In the above reaction formula, R1, Z and n are as defined in the foregoing.)
The compound (b-1) as the material for the synthesis of the aforementioned compound (II) is a member of 1-phenylpiperazines when Y is N or a member of 4-phenylpiperidines when Y is CH. Also, the compound (b-2) as the material for the synthesis of the compound (III) is a member of 4-phenyl-1,2,3,6-tetrahydropyridines.
Illustrative typical examples of the 1-phenylpiperazines are shown in the following; 1-phenylpiperazine, 1-(2-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 1-(2-chlorophenyl)piperazine, 1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine, 1-(4-bromophenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine, 1-(4-methoxyphenyl)piperazine, 1-(2-ethoxyphenyl)piperazine, 1-(2-isopropyloxyphenyl)piperazine, 1-(3-trifluoromethylphenyl)piperazine, 1-(2-methylphenyl)piperazine, 1-(3-methylphenyl)piperazine, 1-(4-methylphenyl)piperazine, 1-(2,3-dimethylphenyl)piperazine, 1-(2,5-dimethylphenyl)piperazine, 1- (2,6-dimethylphenyl) piperazine, 1- (3,4-dimethylphenyl) piperazine, 1-(4-nitrophenyl)piperazine, 1-(4-acetylphenyl)piperazine, 1-(2-acetylphenyl)piperazine, 1-(3-methylphenyl)2-methylpiperazine, 1-(4-chlorophenyl)2-methylpiperazine, 1-(3-methoxyphenyl)2-methylpiperazine, 4-(4-sulfamoyl)-piperazine, 4-(4-carbamoylphenyl)piperazine and the like
Illustrative typical examples of the 4-phenylpiperidines are shown in the following; 4-phenylpiperidine, 4-(4-fluorophenyl)piperidine, 4-(4-chlorophenyl)piperidine, 4-(4-bromophenyl)piperidine, 4-(3-trifluoromethylphenyl)piperidine, 4-(4-chloro-3-trifluoromethylphenyl)piperidine, 4-(2-methoxyphenyl)piperidine and the like.
Illustrative typical examples of the 4-phenyl-1,2,3,6-tetrahydropyridines are shown in the following; 4-phenyl-1,2,3,6-tetrahydropyridine, 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, 4-(2-methoxyphenyl)-1,2,3,6-tetrahydropyridine, 4-(4-methylphenyl)-1,2,3,6-tetrahydropyridine and the like.
The compound (b-3) as the material for the synthesis of the aforementioned compound (IV) is a member of 4-phenylpiperidines in which the 4-position R5 can have the aforementioned substituent groups other than hydrogen atom.
Illustrative examples of such 4-phenylpiperidines include 4-hydroxy-4-phenylpiperidine, 4-cyano-4-phenylpiperidine, 4-methoxy-4-phenylpiperidine, 4-methyl-4-phenylpiperidine, 4-acetyl-4-phenylpiperidine, 4-carboxy-4-phenylpiperidine, 4-methoxycarbonyl-4-phenylpiperidine, 4-(4-chlorophenyl)-4-hydroxypiperidine, 4-(4-bromophenyl)-4-hydroxypiperidine, 4-(3-trifluoromethylphenyl)-4-hydroxypiperidine and the like.
The compound (b-4) as the material for the synthesis of the aforementioned compound (V) is a member of piperazines having a nitrogen-containing heterocyclic ring on the 1-position.
Illustrative examples of such piperazines are shown below;
1-(2-pyridyl)piperazine,
1-(3-trifluoromethylpyridin-2-yl)piperazine,
1-(4-trifluoromethylpyridin-2-yl)piperazine,
1-(5-trifluoromethylpyridin-2-yl)piperazine,
1-(6-trifluoromethylpyridin-2-yl)piperazine, pyrimidin-2-yl-piperazine.
The compound of formula (a-1) as the other one of the materials to be used in the synthesis of the compound of the present invention represented by the formula (I) is produced from commercially available reagents in the following manner. That is, in the case of a compound (a-2) in which R3 and R4 in the formula (a-1) are both hydrogen atoms, 2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (a-2-0) is used as a first reagent, 
and the compound of interest is produced by allowing this reagent to react with a second reagent of the formula (c), Xxe2x80x94(CH2)nxe2x80x94X (wherein X and n are as defined in the foregoing), in an inert solvent in the presence of a base. Preferably, dimethylformamide can be exemplified as the solvent, and sodium hydride as the base.
Examples of the compound (c) include those in which X is a halogen atom such as chlorine atom, bromine atom and iodine atom, and its more preferred examples include 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane and 1,6-dibromohexane. Other examples of the compound (c) include disulfonic acid esters, and 1,3-dimethanesulfonyloxypropane and the like alkylsulfonic acid diesters or 1,4-dibenzenesulfonyloxybutane and the like arylsulfonic acid diesters can be used.
The compound (c) belongs to a so-called reactive intermediate and can be obtained as a synthetic reagent or synthesized from diols represented by a formula HOxe2x80x94(CH2)nxe2x80x94OH (wherein n is an integer of 2 to 6). That is, it can be obtained as a dihalide by allowing diols to react with thionyl chloride or thionyl bromide or as a disulfonate by allowing diols to react with methanesulfonyl chloride or the like alkylsulfonic acid halide or benzenesulfonyl chloride or the like arylsulfonic acid halide. In addition, as another example of the halogenation, a halogenation reaction which is carried out using carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine can also be used.
A compound (a-3) in which R4 of the compound (a-1) is a hydrogen atom and R3 is not a hydrogen atom can be obtained by using a compound (a-0), namely benz[cd]indole-2(1H)-one, as the starting material, allowing the material to react with a compound represented by the formula (d) [wherein X is a halogen atom, a methanesulfonyloxy, ethanesulfonyloxy or the like alkylsulfonic acid ester residue or a benzenesulfonyloxy, p-toluenesulfonyloxy or the like arylsulfonic acid ester residue, and R3 is a lower alkyl or aralkyl group] in the presence of a base to obtain a compound (a-0-1), allowing the resulting compound to undergo its reaction using Raney nickel as a catalyst in an atmosphere of hydrogen to obtain a compound (a-3-0) and then allowing the thus obtained compound to react with the compound (c). 
Examples of the compound (d) shown in the above reaction formula include those in which X is a halogen atom such as chlorine, bromine and iodine, and more preferred examples of the compound (d) include bromomethane, iodomethane, bromoethane, iodoethane, 1-bromo-2-methylpropane, 1-iodo-2-methylpropane, 1-bromopropane and 1-bromobutane. Other examples of the compound (d) include sulfonic acid esters, and methyl methanesulfonate and the like alkylsulfonic acid esters or 1-benzenesulfonyloxyethane and the like arylsulfonic acid esters can be used.
The compound (d) is generally obtained as a commercially available reagent or synthesized from alcohols represented by a formula HOxe2x80x94R3 (wherein R3 is as defined in the foregoing) in the same manner as the case of the compound (c).
As shown in the aforementioned reaction formula, the compound (a-0-1) is converted into the compound (a-3-0) through its catalytic hydrogenation in the presence of Raney nickel. This reaction is carried out after dilution with a polar solvent or a non-polar solvent and progresses under ordinary pressure or a pressurized condition. Examples of the solvent to be used include water, alcohol, acetic acid and the like polar solvents and ether, benzene, hexane and the like non-polar solvents.
A compound (a-4) in which R3of the compound (a-1) is a hydrogen atom and R4 is not a hydrogen atom can be obtained by carrying out substitution reaction of at least one of the 6- to 8-positions of the aromatic ring of the compound (a-2-0), thereby firstly obtaining a compound (a-4-0), and then allowing the thus obtained compound to react with the compound (c), or by carrying out substitution reaction of at least one of the 6- to 8-positions of the aromatic ring of the compound (a-1-0) in which R3 and R4 of the compound (a-1) are hydrogen atoms. 
It is desirable to carry out introduction of a substituent group into the aromatic ring by a well known aromatic electrophilic substitution reaction. Examples of the aromatic electrophilic substitution reaction include halogenation, alkylation and acylation using the Friedel-Crafts reaction, nitration and the like.
In a preferred example of the halogenation, the reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in a solvent such as carbon disulfide, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane and acetic acid in the presence or absence of an appropriate catalyst. Examples of the halogenation agent to be used include fluorine, chlorine, bromine and iodine, as well as unsubstituted or substituted N-fluoropyridinium salts such as 1-fluoropyridinium trifurate and 1-fluoro-2,6-dichloropyridinium tetrafluoroborate, N-fluoro-N-alkyl-sulfonamides such as N-fluoro-N-propyl-p-toluenesulfonamide, N-fluorosulfonimides such as N-fluorobenzenesulfonimide, sodium hypochlorite, N-bromosuccinimide, and the like.
The Friedel-Crafts reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in a solvent such as carbon disulfide, chloroform, dichloromethane, 1,2-dichloroethane and nitrobenzene in the presence of a catalyst. Examples of the alkylation agent to be used include halogenated hydrocarbons, as well as alcohols such as methanol and ethanol and olefin compounds such as propene. Examples of the acylation agent to be used include acyl halides such as acetyl chloride and propyl chloride, as well as acid anhydrides such as acetic anhydride, and carboxylic acids such as acetic acid and propionic acid. Alternatively, an acid chloride derivative is obtained using oxalic acid chloride, triphosgene or the like and then hydrolyzed using water, alcohol, amines and the like to convert it into respective carboxylic acid derivative, ester derivative and amide derivative. Examples of the catalyst to be used desirably include Lewis acids such as aluminum chloride, iron chloride, boron trifluoride, tin chloride and zinc chloride, as well as proton acids such as hydrogen fluoride, sulfuric acid and polyphosphoric acid.
In an example of the nitration, the reaction is carried out using concentrated nitric acid and concentrated sulfuric acid or using nitric acid in water, acetic acid or acetic anhydride solution. In addition, ethyl nitrate and the like nitric acid esters, acetyl nitrate and the like mixed acids and nitronium tetrafluoroborate and the like nitronium salts can also be used.
As occasion demands, the substituent group R4 introduced into the aromatic ring may be converted into other substituent group by a chemical reaction. The reaction may be carried out either before the reaction with the compound (b) or after completion of the reaction with the compound (b).
For example, acetyl group or the like acyl group can be converted into corresponding acyloxy group by allowing it to react with peroxide such as m-chloroperbenzoic acid and pertrifluoroacetic acid in the presence of trifluoroacetic acid or the like acid catalyst as occasion demands, thereby effecting insertion of oxygen atom between the aromatic ring and carbonyl group. Thereafter, the acyloxy group can be converted into hydroxyl group by removing the acyl group through hydrolysis or the like method and then into an alkoxy group by the reaction of methyl iodide or the like alkylation agent in the presence of a base such as potassium carbonate and sodium bicarbonate. Also, methoxycarbonyl group or the like ester group can be converted into carbamoyl group, an amide derivative, a hydrazide derivative, a hydroxamic acid derivative or the like, when it is allowed to react, directly or after its hydrolysis into carboxylic acid, with ammonia, a primary amine, a secondary amine, hydrazine, hydroxylamine or the like via an active ester or the like reactive derivative.
Also, when the compound (I) in which R3 and R4 have substituent groups other than a hydrogen atom is synthesized, it is desirable that the compound (a-3) or (a-3-0) is firstly obtained, substitution of a hydrogen atom on the aromatic ring is carried out in the same manner as described in the foregoing and then the thus treated compound is allowed to react with the compound (b), directly in the former case or after converting it into the compound (a-1) by its reaction with the compound (c) in the latter case.
In addition, the compound (I) can also be synthesized by the following method.
The compound (I) can also be synthesized by the use of an alkene compound represented by a formula CH2xe2x95x90CHxe2x80x94(CH2)n-1xe2x80x94X [wherein n and X are as defined in the foregoing] or using a compound represented by formula: Wxe2x80x94(CH2)nxe2x80x94X [wherein W is a protected hydroxyl group (for example, benzyloxy group, acyloxy group and the like), and n and X are as defined in the foregoing], in stead of the compound (c). That is, as shown in the following reaction formula, 
the compound (I) of interest can be obtained by allowing the compound (a) to react with these compounds in the presence of a base and then allowing osmium tetroxide and sodium periodate to react with the alkenes to effect conversion into an aldehyde compound, or, after de-protection of W, carrying out oxidation to effect conversion into an aldehyde compound and then carrying out reductive aminoalkylation reaction of the aldehyde compound with the compound (b) using sodium triacetoxyborate or the like reducing agent.
In the synthesis of the compound of the present invention, purification of a compound of interest from the reaction mixture is carried out by employing usually used techniques in the field of chemical synthesis, namely by effecting partition extraction of the reaction product into water and an organic solvent which does not optionally mixed with water, such as benzene, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane or the like solvent, and then carrying out concentration, crystallization and the like techniques. Also, as occasion demands, fractional purification may be carried out for example by a column chromatography using alumina or silica gel.
Being an amine, the compound (I) of the present invention exists as a base. In consequence, it forms salts with a number of inorganic and organic acids, and such a property is applied to its provisional forms as pharmaceutical preparations. That is, in its production process, acidification of the compound renders possible its solubilization and extraction purification in a polar solvent such as water so that it can be isolated as a salt having desirable physico-chemical properties, and, in applying it to pharmaceutical preparations, it can form a pharmacologically acceptable salt. Examples of the salt to be formed include acid addition salts with inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid and sulfuric acid or with aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanoic diacids, amino acids and the like, as well as salts derived from aromatic acids, aliphatic and aromatic sulfonic acids and the like nontoxic organic acids. Examples of such acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogensulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, acetate, propionate, tartarate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, glycolate and the like.
These acid addition salts described above are significant also as pharmacologically acceptable pharmaceutical compositions, and it seems that they have advantages as pharmaceutical compositions in terms of the preparation of medicaments and of the dispersing and absorbing abilities when administered to the human body.
A pharmaceutical composition which contains the compound of the present invention as an active ingredient can be administered to human and animals through the route of either oral administration or parenteral administration (for example, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, percutaneous absorption and the like). Thus, the pharmaceutical composition containing the compound of the present invention as an active ingredient can be made into appropriate dosage forms depending on each route of administration.
Illustrative examples of dosage forms include tablets, capsules, powders, granules, syrups and the like as oral preparations and intravenous, intramuscular and the like injections, rectal administration preparations, oleaginous suppositories, aqueous suppositories and the like as parenteral preparations.
Each of these various preparations can be produced in the usual way making use of generally used fillers, disintegrators, binders, lubricating agents, coloring agents and the like.
For example, lactose, glucose, corn starch, sorbitol, crystalline cellulose and the like can be exemplified as the fillers, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like can be cited as the disintegrators, dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like can be exemplified as the binders, and talc, magnesium stearate, polyethylene glycol, hardened plant oil and the like can be exemplified as the lubricating agents. In addition, the aforementioned injections can be produced by further adding a buffer, a pH adjusting agent, a stabilizing agent and the like as occasion demands.
Though the amount of the compound of the present invention in the pharmaceutical composition varies depending on its dosage forms, it may be used in an amount of generally from 0.1 to 50% by weight, preferably from 0.1 to 20% by weight, based on the total composition. Its dose is optionally decided in each case, taking age, body weight, sex, difference in diseases, degree of symptoms and the like of each patient into consideration, but the dose is within the range of generally from 1 to 1,000 mg, preferably from 1 to 300 mg, per day per adult, and the daily dose is administered once a day or by dividing it into several doses per day.
The pharmaceutical composition of the present invention can be used for the treatment or prevention of manic-depressive psychosis, anxiety, schizophrenia, gastrointestinal disease, jet lag and the like.